Easy preparative scale syntheses of labelled xanthines: caffeine, theophylline and theobromine

Abstract

Several easy preparative scale (0.5-1.5 g) syntheses of deuterium labelled caffeine, theophylline and theobromine are described. Some new selective syntheses of theophylline and theobromine have been developed. Labelled xanthines are of great interest in qualitative or quantitative isotope dilution-mass spectrometry, coupled with gas or liquid chromatography, currently performed in anti-doping and forensic laboratories.

Collision‐induced dissociation studies of caffeine in positive electrospray ionisation mass spectrometry using six deuterated isotopomers and one N1‐ethylated homologue

“…Several synthetic routes for the preparation of deuterated caffeine derivatives have been described in the literature. [12,14,21,22] The syntheses of the 1-, 3-, and 7-mono-trideuteromethyl isotopomers 2, 3, and 4, the 1,3,7-tris-trideuteromethyl isotopomer 5 of caffeine and the N-3-ethyl derivative 7 (Fig. 1) were carried out using modified literature procedures.…”

Efficient Access to Deuterated and Tritiated Nucleobase Pharmaceuticals and Oligonucleotides using Hydrogen‐Isotope Exchange

“…To ensure that the labelling was ar esult of the combined action of the Ru nanoparticles and D 2 as an isotopic source,c ontrol experiments using only D 2 Ow ere performed. [14] Flavin adenine dinucleotide (FAD; 13)was also labelled both at the purine and the flavin cores,thus demonstrating the usefulness of the method for the labelling of fragile and structurally complex substrates. Furthermore,t he broad scope of this transformation was demonstrated by the labelling of deoxyadenosine (4), inosine (5), and nucleotides such as AMP (6), c-AMP (7), ADP (8)a nd ATP ( 9).…”

“…[9a, 13] Adenosine (2)a nd guanosine (3)w ere selectively deuterated on the purine core using the same reaction conditions described above ( Figure 2). Remarkably,d espite the coordination ability of phosphate groups for metallic nanoparticles,b oth selectivity and deuterium incorporation remained very high even in the case of ATPw hich contains at risphosphate moiety.I nterestingly,o nly slight changes in deuterium incorporation were observed depending on the pH of the solution for 9 (see Table S1 in the Supporting Information) highlighting the robustness of this new catalytic process.A nalogues like the deuterated xanthines 10, 11,a nd 12,w idely used as internal standards in qualitative or quantitative isotope dilution mass-spectrometry for antidoping controls, [14] were also obtained with ag ood deuterium incorporation and isotopic enrichment on the purine core (1.3 to 3.9 Di ncorporated). As expected, aw eak to average labelling of the most acidic position 8w as obtained without the presence of Ru nanoparticles and D 2 gas.I nterestingly,t he attractive position 2, known to not be prone to back-exchange during biodistribution studies,i se fficiently labelled in the case of 2 using our method.…”

“…Furthermore,t he broad scope of this transformation was demonstrated by the labelling of deoxyadenosine (4), inosine (5), and nucleotides such as AMP (6), c-AMP (7), ADP (8)a nd ATP ( 9). Remarkably,d espite the coordination ability of phosphate groups for metallic nanoparticles,b oth selectivity and deuterium incorporation remained very high even in the case of ATPw hich contains at risphosphate moiety.I nterestingly,o nly slight changes in deuterium incorporation were observed depending on the pH of the solution for 9 (see Table S1 in the Supporting Information) highlighting the robustness of this new catalytic process.A nalogues like the deuterated xanthines 10, 11,a nd 12,w idely used as internal standards in qualitative or quantitative isotope dilution mass-spectrometry for antidoping controls, [14] were also obtained with ag ood deuterium incorporation and isotopic enrichment on the purine core (1.3 to 3.9 Di ncorporated). Fort hose compounds,t he additional labelling of the methyl group can be explained by ar emote CÀHactivation process facilitated by the proximity of the sp 3hybridized carbon center to the surface of the Ru nanocluster after the coordination of the nitrogen in position 9.…”

Synthesis and Biological Evaluation of Xanthine Derivatives on Dipeptidyl Peptidase 4

“…Condensation of methylurea and ethyl cyanoacetate followed by nitrosation gave compound B. 11) Reduction of nitroso group with sodium hydrosulfite yielded compound C. 12) The xanthine ring was formed by the condensation of compound C with glycolic acid. The alkylation at N-7 position was carried out by treatment with R 7 X (X= Cl or Br) and diisopropylethylamine in dimethyl sulfoxide (DMSO).…”